BACKGROUND Lissencephaly(LIS)is a malformation of cortical development with broad gyri,shallow sulci and thickened cortex characterized by developmental delays and seizures.Currently,20 genes have been implicated in L...BACKGROUND Lissencephaly(LIS)is a malformation of cortical development with broad gyri,shallow sulci and thickened cortex characterized by developmental delays and seizures.Currently,20 genes have been implicated in LIS.However,GRP56-related LIS has never been reported.GRP56 is considered one of the causative genes for bilateral frontoparietal polymicrogyria.Here,we report a twin infant with LIS and review the relevant literature.The twins both carried the novel compound heterozygous GPR56 mutations.CASE SUMMARY A 5-mo-old female infant was hospitalized due to repeated convulsions for 1 d.The patient had a flat head deformity that manifested as developmental delays and a sudden onset of generalized tonic-clonic seizures at 5 mo without any causes.The electroencephalography was normal.Brain magnetic resonance imaging revealed a simple brain structure with widened and thickened gyri and shallow sulci.The white matter of the brain was significantly reduced.Patchy long T1 and T2 signals could be seen around the ventricles,which were expanded,and the extracerebral space was widened.Genetic testing confirmed that the patient carried the GPR56 gene compound heterozygous mutations c.228delC(p.F76fs)and c.1820_1821delAT(p.H607fs).The unaffected father carried a heterozygous c.1820_1821delAT mutation,and the unaffected mother carried a heterozygous c.228delC mutation.The twin sister carried the same mutations as the proband.The patient was diagnosed with LIS.CONCLUSION This is the first case report of LIS that is likely caused by mutations of the GPR56 gene.展开更多
AIM: To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS: Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal dise...AIM: To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS: Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE5B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated. RESULTS: We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T6041) in PDE5B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases. CONCLUSION: We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE9B contribute to the genetic heterogeneity of RP.展开更多
BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).Howev...BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).However,the characteristics of nephrotic syndrome(NS)caused by CRB2 mutations have not been described.CASE SUMMARY We report a novel compound heterozygous mutation of the CRB2 gene in two siblings with SRNS.The two siblings had edema,proteinuria,hypoproteinemia and hyperlipidemia.Both their father and mother had normal phenotypes(no history of NS).Whole exon sequencing(WES)of the family showed a novel compound heterozygous mutation,c.2290(exon 8)C>T and c.3613(exon 12)G>A.Glucocorticoid therapy(methylprednisolone pulse therapy or oral prednisone)and immunosuppressive agents(tacrolimus)had no effect.During a 3-year follow-up after genetic diagnosis by WES,proteinuria persisted,but the patient was healthy.CONCLUSION CRB2 mutations related to SRNS often occur in exons 7,10,and 12.Clinical manifestations of SRNS caused by CRB2 mutations are often less severe than in other forms of SRNS.展开更多
BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifest...BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.展开更多
BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar at...BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.展开更多
报告一例常染色体隐性遗传发病的骨质疏松症-假性胶质瘤综合征。先证者女性,23岁,父母非近亲结婚,出生后发现双目失明,婴儿期因发现右眼视网膜母细胞瘤行右眼球摘除术,9岁开始反复发生轻微外力骨折,诊断为成骨不全。查体发现脊柱侧凸畸...报告一例常染色体隐性遗传发病的骨质疏松症-假性胶质瘤综合征。先证者女性,23岁,父母非近亲结婚,出生后发现双目失明,婴儿期因发现右眼视网膜母细胞瘤行右眼球摘除术,9岁开始反复发生轻微外力骨折,诊断为成骨不全。查体发现脊柱侧凸畸形、胸廓畸形、双上肢肘外翻、四肢关节韧带松弛。双能X线吸收检测仪(dual energy X-ray absorptiometry,DXA)骨密度明显低于同龄人,腰椎1-4骨密度Z值-5,左髋骨密度Z值-1.8。X线摄片示全身骨小梁稀疏。Sanger测序显示低密度脂蛋白受体相关蛋白-5(lowdensity lipoprotein receptor-related protein 5,LRP5)基因的6号外显子和23号外显子发生复合杂合突变,导致p.Pro382Leu+p.Cys1611LeufsX33。本文通过文献复习对该病的临床表现和诊疗特点进行讨论及总结,以期帮助临床医生提高对这一疾病的认识。展开更多
Epidermal growth factor receptor(EGFR)mutations are common oncogenic driver mutations in patients with non-small cell lung cancer(NSCLC).The application of EGFR-tyrosine kinase inhibitors(TKIs)is beneficial for patien...Epidermal growth factor receptor(EGFR)mutations are common oncogenic driver mutations in patients with non-small cell lung cancer(NSCLC).The application of EGFR-tyrosine kinase inhibitors(TKIs)is beneficial for patients with advanced and early-stage NSCLC.With the development of next-generation sequencing technology,numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation;however,the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown.Thus,we review the incidence,prognosis,and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.展开更多
Cystic fibrosis（CF） is a severe genetic disease caused by the gene mutation of the cystic fibrosis transmembrane conductance regulator（CFTR） chloride channel. The most common point mutation AF508, which leads to i...Cystic fibrosis（CF） is a severe genetic disease caused by the gene mutation of the cystic fibrosis transmembrane conductance regulator（CFTR） chloride channel. The most common point mutation AF508, which leads to impaired intracellular processing and channel gating of CFTR, appears in about 90% CF patients. The natural compound curcumin was reported to correct the processing defect of AF508-CFTR and proposed as a potential therapeutic drug to cure CF. In the present study, we analyzed the effect of curcumin on AF508-CFTR and demonstrated that curcumin can restore the impaired chloride conductance of AF508 mutant CFTR. The activity is rapid, reversible and cAMP-dependent. However, we couldn＇t reproduce the previously reported correction of the defective membrane trafficking of AF508-CFTR by curcumin. Therefore, curcumin may not be a superior lead compound for developing anti-CF drugs.展开更多
In the present study, we identified the natural compound curcumin to be an effective G551D-CFTR activator by cell-based fluorescent assay and electrophysiological measurement. We demonstrated that curcumin can restore...In the present study, we identified the natural compound curcumin to be an effective G551D-CFTR activator by cell-based fluorescent assay and electrophysiological measurement. We demonstrated that curcumin can restore the impaired chloride conductance of G551D mutant CFTR. The activity is rapid, reversible, and cAMP-dependent. Our study identified a new natural lead compound for the pharmacological therapy of cystic fibrosis caused by G551D mutation of CFTR.展开更多
目的探寻1个中国汉族非综合征型遗传性聋家系的致病原因。方法收集该家系临床资料,采集静脉血后抽提DNA,通过Sanger测序对三大常见耳聋基因(GJB2、SLC26A4、线粒体DNA 12SrRNA)全序列进行筛查以排除致病突变,通过靶向捕获二代测序对目...目的探寻1个中国汉族非综合征型遗传性聋家系的致病原因。方法收集该家系临床资料,采集静脉血后抽提DNA,通过Sanger测序对三大常见耳聋基因(GJB2、SLC26A4、线粒体DNA 12SrRNA)全序列进行筛查以排除致病突变,通过靶向捕获二代测序对目前所有已知耳聋基因进行检测并寻找该患者的可疑致病基因,并通过Sanger测序对变异进行验证。结果该家系中先证者听力表型为中度听力障碍,其姐姐为中重度听力障碍,其父母听力正常,对先证者进行三大耳聋基因筛查未见可疑致病突变,通过靶向捕获二代测序及Sanger测序验证发现OTOGL基因截短类型的复合杂合突变是该家系高度可能的致病原因,先证者及其姐姐均携带OTOGL基因c.2833C>T(p.Arg945*)/c.6467C>A(p.Ser2156*)复合杂合突变,分别来自其父母。根据美国医学遗传与基因组学会(American College of medical genetics and genomics,ACMG)遗传变异分类标准与指南,c.2833C>T(p.Arg945*)与c.6467C>A(p.Ser2156*)变异均被判定为致病性变异,前者首次被报道与遗传性聋相关。结论OTOGL基因c.2833C>T(p.Arg945*)与c.6467C>A(p.Ser2156*)复合杂合变异高度可能是该家系耳聋的致病基因。展开更多
基金Supported by the Six Talent Peaks Project in Jiangsu Province,No.2016-YY-055.
文摘BACKGROUND Lissencephaly(LIS)is a malformation of cortical development with broad gyri,shallow sulci and thickened cortex characterized by developmental delays and seizures.Currently,20 genes have been implicated in LIS.However,GRP56-related LIS has never been reported.GRP56 is considered one of the causative genes for bilateral frontoparietal polymicrogyria.Here,we report a twin infant with LIS and review the relevant literature.The twins both carried the novel compound heterozygous GPR56 mutations.CASE SUMMARY A 5-mo-old female infant was hospitalized due to repeated convulsions for 1 d.The patient had a flat head deformity that manifested as developmental delays and a sudden onset of generalized tonic-clonic seizures at 5 mo without any causes.The electroencephalography was normal.Brain magnetic resonance imaging revealed a simple brain structure with widened and thickened gyri and shallow sulci.The white matter of the brain was significantly reduced.Patchy long T1 and T2 signals could be seen around the ventricles,which were expanded,and the extracerebral space was widened.Genetic testing confirmed that the patient carried the GPR56 gene compound heterozygous mutations c.228delC(p.F76fs)and c.1820_1821delAT(p.H607fs).The unaffected father carried a heterozygous c.1820_1821delAT mutation,and the unaffected mother carried a heterozygous c.228delC mutation.The twin sister carried the same mutations as the proband.The patient was diagnosed with LIS.CONCLUSION This is the first case report of LIS that is likely caused by mutations of the GPR56 gene.
基金Supported by the Chinese National Program on Key Basic Research Project(973 Program,No.2013CB967502)the Natural Science Foundation of China(No.81201181/H1818)+2 种基金Zhejiang Provincial&Ministry of Health Research Fund for Medical Sciences(No.2016KYA145)Wenzhou City Grant(No.Y20140633)Chinese National Training Programs of Innovation and Entrepreneurship for Undergraduates(No.20130343005)
文摘AIM: To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS: Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE5B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated. RESULTS: We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T6041) in PDE5B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases. CONCLUSION: We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE9B contribute to the genetic heterogeneity of RP.
文摘BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).However,the characteristics of nephrotic syndrome(NS)caused by CRB2 mutations have not been described.CASE SUMMARY We report a novel compound heterozygous mutation of the CRB2 gene in two siblings with SRNS.The two siblings had edema,proteinuria,hypoproteinemia and hyperlipidemia.Both their father and mother had normal phenotypes(no history of NS).Whole exon sequencing(WES)of the family showed a novel compound heterozygous mutation,c.2290(exon 8)C>T and c.3613(exon 12)G>A.Glucocorticoid therapy(methylprednisolone pulse therapy or oral prednisone)and immunosuppressive agents(tacrolimus)had no effect.During a 3-year follow-up after genetic diagnosis by WES,proteinuria persisted,but the patient was healthy.CONCLUSION CRB2 mutations related to SRNS often occur in exons 7,10,and 12.Clinical manifestations of SRNS caused by CRB2 mutations are often less severe than in other forms of SRNS.
基金Supported by the Natural Science Foundation of Shandong Province,No.ZR2019MH060。
文摘BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.
文摘BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.
文摘报告一例常染色体隐性遗传发病的骨质疏松症-假性胶质瘤综合征。先证者女性,23岁,父母非近亲结婚,出生后发现双目失明,婴儿期因发现右眼视网膜母细胞瘤行右眼球摘除术,9岁开始反复发生轻微外力骨折,诊断为成骨不全。查体发现脊柱侧凸畸形、胸廓畸形、双上肢肘外翻、四肢关节韧带松弛。双能X线吸收检测仪(dual energy X-ray absorptiometry,DXA)骨密度明显低于同龄人,腰椎1-4骨密度Z值-5,左髋骨密度Z值-1.8。X线摄片示全身骨小梁稀疏。Sanger测序显示低密度脂蛋白受体相关蛋白-5(lowdensity lipoprotein receptor-related protein 5,LRP5)基因的6号外显子和23号外显子发生复合杂合突变,导致p.Pro382Leu+p.Cys1611LeufsX33。本文通过文献复习对该病的临床表现和诊疗特点进行讨论及总结,以期帮助临床医生提高对这一疾病的认识。
基金supported by grants from the National Natural Science Foundation of China(No.81874052)Jilin Province Health Talents Special Project(No.JLSWSRCZX2020-0023)the Technology Development Program of Jilin Province(No.20190303146SF)to J.Cui.
文摘Epidermal growth factor receptor(EGFR)mutations are common oncogenic driver mutations in patients with non-small cell lung cancer(NSCLC).The application of EGFR-tyrosine kinase inhibitors(TKIs)is beneficial for patients with advanced and early-stage NSCLC.With the development of next-generation sequencing technology,numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation;however,the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown.Thus,we review the incidence,prognosis,and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.
基金Supported by the National Natural Science Foundation for Distinguished Young Scholars(No30325011)National Natural Science Foundation of China(Nos30570864 and 30670477)Program for New Century Excellent Talents in University(No NCET-07-0406)
文摘Cystic fibrosis（CF） is a severe genetic disease caused by the gene mutation of the cystic fibrosis transmembrane conductance regulator（CFTR） chloride channel. The most common point mutation AF508, which leads to impaired intracellular processing and channel gating of CFTR, appears in about 90% CF patients. The natural compound curcumin was reported to correct the processing defect of AF508-CFTR and proposed as a potential therapeutic drug to cure CF. In the present study, we analyzed the effect of curcumin on AF508-CFTR and demonstrated that curcumin can restore the impaired chloride conductance of AF508 mutant CFTR. The activity is rapid, reversible and cAMP-dependent. However, we couldn＇t reproduce the previously reported correction of the defective membrane trafficking of AF508-CFTR by curcumin. Therefore, curcumin may not be a superior lead compound for developing anti-CF drugs.
基金National Natural Science Fund for Distinguished Young Scholars(No.30325011)National Natural Science Foundation of China(Nos.30470405, 30570864, 30670477)+1 种基金Distinguished Young Scholars Fund of Jilin Province (No.20030112) Excellent Young Teachers Program of Ministry of Education, China
文摘In the present study, we identified the natural compound curcumin to be an effective G551D-CFTR activator by cell-based fluorescent assay and electrophysiological measurement. We demonstrated that curcumin can restore the impaired chloride conductance of G551D mutant CFTR. The activity is rapid, reversible, and cAMP-dependent. Our study identified a new natural lead compound for the pharmacological therapy of cystic fibrosis caused by G551D mutation of CFTR.
文摘目的探寻1个中国汉族非综合征型遗传性聋家系的致病原因。方法收集该家系临床资料,采集静脉血后抽提DNA,通过Sanger测序对三大常见耳聋基因(GJB2、SLC26A4、线粒体DNA 12SrRNA)全序列进行筛查以排除致病突变,通过靶向捕获二代测序对目前所有已知耳聋基因进行检测并寻找该患者的可疑致病基因,并通过Sanger测序对变异进行验证。结果该家系中先证者听力表型为中度听力障碍,其姐姐为中重度听力障碍,其父母听力正常,对先证者进行三大耳聋基因筛查未见可疑致病突变,通过靶向捕获二代测序及Sanger测序验证发现OTOGL基因截短类型的复合杂合突变是该家系高度可能的致病原因,先证者及其姐姐均携带OTOGL基因c.2833C>T(p.Arg945*)/c.6467C>A(p.Ser2156*)复合杂合突变,分别来自其父母。根据美国医学遗传与基因组学会(American College of medical genetics and genomics,ACMG)遗传变异分类标准与指南,c.2833C>T(p.Arg945*)与c.6467C>A(p.Ser2156*)变异均被判定为致病性变异,前者首次被报道与遗传性聋相关。结论OTOGL基因c.2833C>T(p.Arg945*)与c.6467C>A(p.Ser2156*)复合杂合变异高度可能是该家系耳聋的致病基因。
